The present invention relates generally to novel organic synthetic methodology and its application for providing compounds that are useful as inhibitors of 11β-hydroxy steroid dehydrogenase type 1.
Hydroxysteroid dehydrogenases (HSDs) regulate the occupancy and activation of steroid hormone receptors by converting steroid hormones into their inactive metabolites. For a recent review, see Nobel et al., Eur. J. Biochem. 2001, 268:4113-4125.
There exist numerous classes of HSDs. The 11-beta-hydroxysteroid dehydrogenases (11β-HSDs) catalyze the interconversion of active glucocorticoids (such as cortisol and corticosterone), and their inert forms (such as cortisone and 11-dehydrocorticosterone). The isoform 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is expressed in liver, adipose tissue, brain, lung and other glucocorticoid tissue and is a potential target for therapy directed at numerous disorders that may be ameliorated by reduction of glucocorticoid action, such as diabetes, obesity and age-related cognitive dysfunction. Seckl, et al., Endocrinology, 2001, 142:1371-1376.
The various isozymes of the 17-beta-hydroxysteroid dehydrogenases (17β-HSDs) bind to androgen receptors or estrogen receptors and catalyze the interconversion of various sex hormones including estradiol/estrone and testosterone/androstenedione. To date, six isozymes have been identifed in humans and are expressed in various human tissues including endometrial tissue, breast tissue, colon tissue, and in the testes. 17-beta-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) is expressed in human endometrium and its activity has been reported to be linked to cervical cancer. Kitawaki et al., J. Clin. Endocrin. Metab., 2000, 85:1371-3292-3296. 17-beta-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is expressed in the testes and its modulation may be useful for the treatment of androgen-related disorders.
Androgens and estrogens are active in their 17β-hydroxy configurations, whereas their 17-keto derivatives do not bind to androgen and estrogen receptors and are thus inactive. The conversion between the active and inactive forms (estradiol/estrone and testosterone/androstenedione) of sex hormones is catalyzed by members of the 17β-HSD family. 17β-HSD1 catalyzes the formation of estradiol in breast tissue, which is important for the growth of malignant breast tumors. Labrie et al., Mol. Cell. Endocrinol. 1991, 78:C113-C118. A similar role has been suggested for 17β-HSD4 in colon cancer. English et al., J. Clin. Endocrinol. Metab. 1999, 84:2080-2085. 17β-HSD3 is almost exclusively expressed in the testes and converts androstenedione into testosterone. Deficiency of this enzyme during fetal develoment leads to male pseudohermaphroditism. Geissler et al., Nat. Genet. 1994, 7:34-39. Both 17β-HSD3 and various 3α-HSD isozymes are involved in complex metabolic pathways which lead to androgen shuffles between inactive and active forms. Penning et al., Biochem. J. 2000, 351:67-77. Thus, modulation of certain HSDs can have potentially beneficial effects in the treatment of androgen- and estrogen-related disorders.
The 20-alpha-hydroxysteroid dehydrogenases (20α-HSDs) catalyze the interconversion of progestins (such as between progesterone and 20α-hydroxy progesterone). Other substrates for 20α-HSDs include 17α-hydroxypregnenolone or 17α-hydroxyprogesterone, leading to 20α-OH steroids. Several 20α-HSD isoforms have been identified and 20α-HSDs are expressed in various tissues, including the placenta, ovaries, testes and adrenals. Peltoketo, et al., J. Mol. Endocrinol. 1999, 23:1-11.
The 3-alpha-hydroxysteroid dehydrogenases (3α-HSDs) catalyze the interconversion of the androgens dihydrotestosterone (DHT) and 5α-androstane-3α;17β-diol and the interconversion of the androgens DHEA and androstenedione and therefore play an important role in androgen metabolism. Ge et al., Biology of Reproduction 1999, 60:855-860.
Inhibitors of 11β-HSD1, and in particular C5-substituted 2-amino thiazolinones as shown below, have been linked to the treatment of a variety of diseases.

The diseases include, for example, diabetes, obesity and related cardiovascular risk factors, cognitive diseases such as dementia, immunomodulation disorders, glaucoma, and inflammatory diseases. See U.S. patent application No. Ser. 11/135,662, filed on May 24, 2005.
A subset of such inhibitors features unsaturated C-5 substituents, such as aryl groups, which can be introduced in principle via lengthy and traditional syntheses onto parent 2-amino thiazolinones. The diversity of available aryl substrates in particular for C-5 arylation would portend a ready library of C5-aryl substituted 2-amino thiazolinones. However, the existing synthetic methodology for installing the aryl substituent hampers efficient structure-activity relationship (SAR) studies, thereby rendering extant methods not practical in the discovery of 11β-HSD1 inhibitors.
Metal-catalyzed α-arylation of carbonyl compounds would generally suggest a more direct and potentially more efficient route to the desired C5-arylated 2-amino thiazolinones. See S. Lee et al. J. Am. Chem Soc. (2001) 123, 8410-8411; T. Hamada et al. J Am. Chem. Soc. (2002) 124, 1261-1268; M. Kawatsura et al. J Am. Chem. Soc.(1999) 121, 1473-1478; and S. R. Stauffer et al. J. Am. Chem. Soc. (2001), 123, 4641-4642. However, the arylation of heterocycles is relatively unexplored, and the 2-amino thiazolinone scaffold in particular poses regiospecificity problems by virtue of the presence of multiple candidate reaction sites in addition to the desired C-5 position:

Therefore, a need exists for a relatively short and efficient method to regioselectively derivatize, and in particulate arylate, a 2-amino thiazolinone at the C-5 position.